This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: The overall objective of this study is to perform baseline and repeat assessments over time of the metabolic and immunologic status of individuals at risk for T1D in order: a) To characterize their risk for developing T1D, b) To describe the pathogenetic evolution of T1D, and c) To increase the understanding of the pathogenetic factors involved in the development of T1D. SUMMARY: The TrialNet Natural History Study of the Development of T1D is divided into three phases: Screening (Phase 1), Baseline Risk Assessment (Phase 2) and Follow-up Risk Assessments (Phase 3). Each of these phases will require separate informed consent for entry. A prospective cohort design will be used for the study. Phase 1 involves screening for the presence of autoantibodies associated with T1D. Individuals who are positive for one or more of the same biochemical autoantibodies (anti-GAD65, anti-ICA512 or IAA) on two separate blood samples during screening (i.e., confirmed autoantibody positive) will be eligible for entry into Phase 2 of the study, the baseline risk assessment. In addition, individuals who are positive for at least two biochemical autoantibodies on the first blood sample obtained during screening will be eligible for entry into Phase 2. These subjects will have the option of providing the second sample for autoantibody confirmation during Phase 2 or providing the second sample before proceeding to Phase 2. Since TrialNet is a consortium that will continue to develop protocols for studying the etiology and prevention of T1D, it is possible that individuals who do not qualify for Phase 2 might still be eligible for other studies. Therefore, they may be contacted in the future so that they can be informed of new studies. In addition, they will be contacted periodically to learn if they have developed T1D. Individuals under the age of 18 years, who do not qualify for Phase 2, will be invited back for rescreening on an annual basis until they reach their 18th birthday. The baseline risk assessment will include an OGTT, the measurement of HbA1c, testing for ICA, and HLA typing (in consenting participants). Participants with protective HLA alleles will not be excluded from this study. In certain cases, a 20 minute IVGTT for First Phase Insulin Response (FPIR) will also be performed. Upon completion of Phase 2, participants will be classified into one of three risk categories for the occurrence of T1D within five years: 50%. The risk categories will be defined according to the OGTT results, number of confirmed positive biochemical autoantibodies, ICA positivity, and when required, IVGTT results. Participants will be informed of their risk categories when all test results are available. Individuals who participate in Phase 2 will also be offered the opportunity (through written consent) to enter Phase 3 for follow-up risk assessments. They will be seen at six-month intervals for five years or until the end of the study. At each visit, procedures will include an OGTT, collection of blood for autoantibody testing and measurement of HbA1c levels. IVGTTs will not be performed. Although there will not be a formal categorization of risk following each assessment, participants will be informed of their test results upon request. During each phase of the study, residual blood samples (and DNA samples in Phase 2) from consenting participants will be stored indefinitely at a TrialNet core laboratory and/or an NIDDK repository site for future immunologic and metabolic assessments that bear upon mechanisms of [unreadable]x-cell destruction, and to obtain additional information about genetic markers associated with risk for the development of T1D. Subjects may still participate in all phases of the study even if they choose not to give consent for storage. Mechanistic samples will also be collected at Phases 2 and 3 at Clinical Centers participating in the Protocol Amendment for the collection of samples for storage for mechanistic studies. Individuals who qualify for prevention trials based on their risk assessments will be invited to participate in those trials as they become available. Individuals who enter a prevention trial will be followed according to the protocol of that trial. However, pertinent data accrued during the trial (conditional upon treatment status in the trial) such as the development of T1D, may be incorporated into the database for this study. The primary study outcome is diabetes mellitus (T1D) as defined by the American Diabetes Association (ADA) criteria. For most subjects, this will be based upon the results of an OGTT in the absence of symptomatic hyperglycemia. Confirmation of a diagnosis of diabetes by a second OGTT test in asymptomatic individuals will be required. Individuals who are hospitalized at diagnosis will be assessed through medical records.